赖氨酸特异性去甲基化酶1介导的经典Wnt信号通路在肿瘤领域的研究进展

Research progress of lysine-specific demethylase 1-mediated classical Wnt/β-catenin signaling pathway in cancers

作为全球性公共卫生问题,肿瘤是当今世界危害人类健康的主要疾病之一。根据2019年国家癌症中心发布的全国最新癌症数据统计,2015年我国共新发恶性肿瘤392.9万例,死亡约为233.8万例,发病率约为285.83/10万,病死率约为170.05/10万。肿瘤的发生、发展是一个多因素、多基因、多阶段渐进性累积的演变过程,涉及肿瘤的转化、生存、增殖、侵袭、血管生成和转移。在这个过程中伴随着遗传基因和表观遗传的变化:致癌基因、抑癌基因、错配修复基因、细胞黏附分子等在DNA、RNA和蛋白质水平发生改变。虽然近年来肿瘤诊断与治疗技术不断取得进步,但大多数患者就诊时已处于晚期状态,总体预后较差。因此探索肿瘤的发病机制,寻找更为有效的预防治疗手段具有重要意义。现有研究表明,表观遗传学改变在肿瘤发生、发展及侵袭转移中意义重大。目前已知的表观遗传修饰主要包括组蛋白修饰、DNA甲基化、核小体重塑、非编码RNA等。在真核生物中,组蛋白修饰包括了乙酰化、甲基化、磷酸化、核糖化及泛素化等。同其它组蛋白修饰一样,组蛋白甲基化是一个动态可逆的过程。赖氨酸特异性去甲基化酶1(LSD1)能够特异性催化组蛋白H3第4位赖氨酸(H3K4)和第9位赖氨酸(H3K9)的脱一甲基、二甲基反应,并与组蛋白去乙酰化酶相互作用,起到转录阻遏物的作用。该酶对哺乳动物生长发育至关重要并参与多种生物学过程,包括细胞分化、异染色质的形成、细胞内DNA甲基化状态的合理维持以及诱导多能干细胞形成等。目前证实LSD1在多种恶性肿瘤组织中高度表达,在肿瘤的发生、发展及耐药性产生中起到重要作用。Wnt信号通路是一条在进化上高度保守的信号通路,对细胞增殖、分化、迁移及凋亡起着重要作用,Wnt信号通路关键分子的基因突变在肿瘤的发生、发展过程中具有重要作用。虽然LSD1和Wnt信号通路都与肿瘤发生、发展有关,但两者之间是否存在联系尚未阐明。近年来越来越多的研究表明,LSD1可通过调节经典Wnt信号通路的活性影响肿瘤的发生、发展。笔者就LSD1介导的经典Wnt信号通路在肿瘤领域的研究进展作一综述。

As a global public health issue,cancer is one of the major diseases that endanger human health in the world today.According to the latest cancer statistics released by the National Cancer Center in 2019,there were 3.929 million new patients with malignant tumor in China in 2015,with a death rate of 2.338 million,an incidence rate of 2.8583/100000 and a mortality rate of 1.705/100000.The occurrence and development of tumor is a multi-factor,multi-gene,multi-stage progressive cumulative evolution process,involving tumor transformation,survival,proliferation,invasion,angiogenesis and metastasis.This process is accompanied by genetic and epigenetic changes:oncogenes,tumor suppressor genes,mismatch repair genes,cell adhesion molecules are changed at DNA,RNA and protein levels.Although tumor diagnosis and treatment techniques have made continuous progress in recent years,most patients are already in advanced stage and the overall prognosis is poor.So,it is significant to explore the pathogenesis of cancer and find more effective prevention and treatment methods.Existing researches show that epigenetic changes are of great significance in tumor occurrence,development,invasion and metastasis.It’s known that epigenetic modifications mainly include histone modification,DNA methylation,nucleosome remodeling,non-coding RNA,etc.In eukaryotes,histone modification includes acetylation,methylation,phosphorylation,ribosylation and ubiquitination,etc.Like other histone modifications,histone methylation is a dynamic and reversible process.Lysine-specific demethylase 1(LSD1)can specifically catalyze the demethylation and dimethyl reactions of lysine at position 4(H3K4)and lysine at position 9(H3K9)of histone H3,and interact with histone deacetylase to act as a transcription repressor.This enzyme is crucial to the growth and development of mammals and participates in a variety of biological processes,including cell differentiation,formation of heterochromatin,reasonable maintenance of DNA methylation status in cells and induction of formation of pluripotent stem cells,etc.At present,it is confirmed that LSD1 is highly expressed in various malignant tumor tissues and plays an important role in the occurrence,development and drug resistance of tumors.Wnt signaling pathway is a highly conserved signaling pathway in evolution,which plays an important role in cell proliferation,differentiation,migration and apoptosis.Gene mutation of key molecules of Wnt signaling pathway plays an important role in the occurrence and development of tumors.Although LSD1 and Wnt signaling pathways are both related to tumor occurrence and development,whether there is a link between them has not been clarified.In recent years,more and more studies have shown that LSD1 can affect the occurrence and development of tumors by regulating the activity of classical Wnt signaling pathway.In this review,the authors summarize the new research findings in the LSD1-mediated Wnt/β-catenin signaling pathway in cancers.